Structural basis for transcription inhibition by tagetitoxin.

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Vassylyev DG, Svetlov V, Vassylyeva MN, Perederina A, Igarashi N, Matsugaki N, Wakatsuki S, Artsimovitch I

Structural basis for transcription inhibition by tagetitoxin.

Nat Struct Mol Biol. 2005 Dec;12(12):1086-93. Epub 2005 Nov 6.

PubMed ID

16273103 [ View in PubMed

]

Abstract

Tagetitoxin (Tgt) inhibits transcription by an unknown mechanism. A structure at a resolution of 2.4 A of the Thermus thermophilus RNA polymerase (RNAP)-Tgt complex revealed that the Tgt-binding site within the RNAP secondary channel overlaps that of the stringent control effector ppGpp, which partially protects RNAP from Tgt inhibition. Tgt binding is mediated exclusively through polar interactions with the beta and beta' residues whose substitutions confer resistance to Tgt in vitro. Importantly, a Tgt phosphate, together with two active site acidic residues, coordinates the third Mg(2+) ion, which is distinct from the two catalytic metal ions. We show that Tgt inhibits all RNAP catalytic reactions and propose a mechanism in which the Tgt-bound Mg(2+) ion has a key role in stabilization of an inactive transcription intermediate. Remodeling of the active site by metal ions could be a common theme in the regulation of catalysis by nucleic acid enzymes.

DrugBank Data that Cites this Article

Drugs

Tagetitoxin

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tagetitoxin	DNA-directed RNA polymerase subunit beta	Protein	Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)	Unknown	Not Available	Details
Tagetitoxin	DNA-directed RNA polymerase subunit beta'	Protein	Thermus thermophilus (strain HB8 / ATCC 27634 / DSM 579)	Unknown	Not Available	Details

Polypeptides

Name	UniProt ID
RNA polymerase sigma factor SigA	Q5SKW1	Details